Hereditary ectodermal dysplasia is an inherited disorder that affects the development of ectodermally derived structures, such as hair, teeth and sweat glands. The hidrotic form of the disease is characterized by poorly developed teeth and hair. The anhidrotic or hypohidrotic form of the disease further affects the development of sweat glands, which interferes with the ability to sweat, and the maintenance of thermoregulatory homeostasis. Both X-linked and autosomal dominant and recessive forms of the disease have been described.
X-linked hypohidrotic ectodermal dysplasia (XLHED; McKusick's number 305100), the most common form of the ectodermal dysplasias, results in the abnormal development of teeth, hair and eccrine sweat glands. Identification of the gene that is defective in this disease would help explain the molecular basis of XLHED, as well as the molecular mechanisms involved in normal tooth, hair and eccrine sweat gland development. Identification of the gene would also permit mutation testing for XLHED in potentially affected males and carrier females.
Heterozygote carriers of XLHED may have minor or moderate degrees of hypodontia, hypotrichosis and hypohidrosis, although many show no obvious clinical manifestations. This clinical variation, presumably caused by random X-inactivation (Lyonization), makes accurate diagnosis of carrier females difficult. Although indirect testing for carrier status is possible by linkage analysis in informative families (Zonana, 1993, Semin Dermatol 12:241–6), carrier detection by this method is impossible in families with single affected individuals, male or female, whose disorder may be the result of a de novo mutation. Detection of mutations within the EDA1 gene would also be advantageous in families with only a single affected sibship, because a rarer autosomal recessive form of the disorder (ARHED) is clinically indistinguishable from XLHED in affected males.
A gene identified as EDA1 was isolated by positional cloning (Kere et al., 1996, Nature Genet. 13:409–416). A single 858 bp cDNA, representing a full length transcript composed of two exons, was identified from an adult sweat gland cDNA library. In situ analysis showed that the EDA1 gene was expressed in hair follicles and the epidermis of adult skin. The putative gene product is a 135 amino acid protein, which has no clear homology to other proteins (see U.S. Pat. No. 5,700,926). The protein is predicted to contain a single transmembrane domain, and fractionation studies of transfected cell lines showed that the protein product is localized to the plasma membrane (Ezer et al., 1997, Hum. Mol. Genet. 6:1581–7). Yeast artificial chromosomes (YACs) containing at least a portion of the human EDA1 gene were disclosed in U.S. Pat. No. 5,556,786.
A syndrome similar to HED, with anhidrosis and absence of sweat glands, is known in the mouse, in which the mutant gene is called Tabby (Ta). Consistent with the map position in humans, the Ta gene has been mapped in the syntenically corresponding region in the X chromosome of the mouse (Brockdorff et al., 1991, Genomics 10:17–22). The Tabby phenotype is indistinguishable from that seen for mutations in downless, another spontaneous mouse mutation identified in the late 1950s on the A/H strain (Philips, 1960, Mouse News Letter 23:29). Tabby and downless mice have abnormally shaped or absent teeth (Grüneberg, 1965, J. Embryol. Exp. Morph. 14:137–59), missing sweat glands and absence of some hair types (Sundberg. 1994. The Downless (dl) and Sleek (D1Sleek) mutations, Chromosome 10. In Maibach. H. I. (ed). Handbook of mouse mutations with skin and hair abnormalities. CRC Press, Inc., Boca Raton, Fla. 241–229.).